Piperazinylcarbonylquinolines and -isoquinolines

ABSTRACT

Compound of the formula (I) in which R 1 , R 2  and alk are as defined in Claim 1, are potent 5-HT 2A  antagonist and are suitable for the treatment of psychoses, schizophrenia, depression, neurological disorders, memory disorders, Parkinson&#39;s disease, amyotrophic lateral sclerosis, Alzheimer&#39;s disease, Hutington&#39;s disease, eating disorders, such as bulimia, anorexia nervosa, premenstrual syndrome and/or for positively influencing obsessive-compulsive disorder (OCD).

FIELD OF THE INVENTION

[0001] The present invention relates to Glucocerebrosidase (GCR)bifunctional fusion proteins (GCR fusion proteins) consistingessentially of an Immunoglobulin (Ig) molecule (whole antibody, an Igheavy or light chain or a fragment thereof) and a protein (the termincludes also oligopeptides) having the biological activity of GCR(GCR-like protein), for enzyme replacement therapy and/or augmentationof glycolipid metabolism by the administration of bifunctional fusionproteins using a therapy based on the treatment of glycolipid storagedisorders such as Gaucher's, Fabry's and Tay-Sachs diseases.

[0002] By selective altering of the amino acid sequences of the Igmoiety, GCR fusion proteins with improved properties, e.g. enhancedstability, can be obtained. Furthermore, fusion proteins can beprovided, wherein shortened versions of GCR and the Ig chain are used.

[0003] The present invention relates also to pharmaceutical compositionsand therapeutic methods and systems comprising such GCR fusion proteinsand methods of treating Gaucher's disease or another disease caused byglycolipid storage disorders, such as Fabry's and Tay-Sachs disease,comprising administering to a subject afflicted with this disease, apharmaceutical composition comprising a therapeutic amount ofrecombinantly produced GCR fusion protein in a pharmaceuticallyacceptable carrier.

BACKGROUND

[0004] The administration of exogenous β-glucosidase to treat diseasescaused by glycolipid storage disorders like Gaucher's, Tay-Sachs' orFabry's disease as attempts of enzyme augmentation in an organismsuffering from such a disease It has been found that the compounds ofthe formula I and their physiologically acceptable salts and solvatesare well tolerated and have valuable pharmacological properties sincethey have actions on the central nervous system. Surprisingly, thecompounds have selective affinity to 5-HT_(2A) receptors. In particular,they are selective 5-HT_(2A) antagonists.

[0005] The substances specified in this application are selective5-HT_(2A) antagonists. 5-HT_(2A) antagonists exhibit clinicallyantipsychotic activity with no or with minimal side effects.Accordingly, the substances of this application are to be regarded asantipsychotics having few side effects. They can in addition be used inthe treatment of neurological illnesses attributable to disturbances inserotonergic transmission, such as depresssion, anxiety states, panicattacks, obsessive-compulsive disorders, pain, sleep disturbances,sleeplessness, eating disorders, such as anorexia nervosa, bulimia,addictive behaviour, dependence on certain addiction-causing substances,such as LSD and MDMA, cardiovascular disorders, such as various anginaillnesses, Reynaud's syndrome, intermittent claudication, cardiac orperipheral vascular spasms, fibromyalgia, cardiac arrhythmia andthrombotic illnesses, since the substances inhibit blood plate-letaggregation. In combination with classical or atypical neuroleptics, theside effects can be suppressed. Owing to the reduction in ocularpressure, the substances can also be employed in glaucoma therapy. Toxicsymptoms caused by poisoning with, for example, ergovalin can besuppressed using the substances.

[0006] For in-vitro detection of the affinity to 5-HT_(2A) receptors,the following test (Example Al), for example, can be used. The 5-HT_(2A)receptors are exposed both to [³H]ketanserine (a substance which isknown for its affinity to the receptor) and also to the test compound.The decrease in the affinity of [³H]ketanserine to the receptor is anindication of the affinity of the test substance to the 5-HT_(2A)receptor. The detection is carried out analogously to the description byJ. E. Leysen et al., Molecular Pharmacology, 1982, 21: 301-314, or asalso described, for example, in EP 0320983.

[0007] The effectiveness of the compounds according to the invention as5-HT_(2A) receptor antagonists can be measured in vitro analogously toW. Feniuk et al., Mechanisms of 5-hydroxytryptamine-inducedvasoconstriction, in: The Peripheral Actions of 5-Hydroxytryptamine, ed.Fozard J. R., Oxford University Press, New York, 1989, p. 110. Thus, thecontractility of-the rat tail artery caused by 5-hydroxytryptamine ismediated by 5-HT_(2A) receptors. For the test system, vessel ringsprepared from the ventral rat tail artery are subjected to perfusion inan organ bath containing an oxygen-saturated solution. By introducingincreasing concentrations of 5-hydroxytryptamine into the solution, aresponse is obtained to the cumulative concentration of 5-HT. The testcompound is then added to the organ bath in suitable concentrations, anda second concentration curve for 5-HT is measured. The strength of thetest compound in shifting the 5-HT-induced concentration curve to higher5-HT concentrations is a measure of the 5-HT_(2A) receptor antagonisticproperty in vitro.

[0008] The 5-HT_(2A)-antagonistic property can be determined in vivoanalogously to M. D. Serdar et al., Psychopharmacology, 1996, 128:198-205.

[0009] Other compounds which likewise exhibit 5-HT₂antagonistic actionsare described, for example, in EP 0320983.

[0010] Similar piperazine derivatives having antiarrhythmic propertiesare disclosed, for example, in EP 0431944 and EP 0431945.

[0011] 5-Isoquinolinesulfonamides are described by A. Morikawa et al. inChem. Pharm. Bull. 1992, 40, 770-3, or in EP 61673 as vasodilators.

[0012] M. Ohashi et al. in JP 631761177 describe piperazinesulfonylderivatives as decolourising ag nts.

[0013] Selective antagonists at the 5-HT_(2A) receptor can preferably beemployed against 5-HT₂ receptor antagonists. This is because 5-HT₂receptor antagonists also bind to other receptor sub-types of the 5-HT₂group, such as, for example, to the 5-HT_(2C) receptor. It is now beingdiscussed that a 5-HT_(2C) receptor antagonism may cause undesiredweight gain (E. Richelson and T. Souder, Life Sci. 2000, 68, 29-39).Selective 5-HT_(2A) receptor antagonists do not induce this effect.

[0014] The compounds of the formula I are suitable both in veterinaryand in human medicine for the treatment of disturbances in the functionof the central nervous system and of inflammations. They can be used forthe prophylaxis and combating of the consequences of cerebral infarctionphenomena (apoplexia cerebri), such as strokes and cerebral ischemia,and for the treatment of extrapyramidal motor and psychic side effectsof neuroleptics and of Parkinson's disease, for the treatment ofParkinson's disease in general, for the acute and symptomatic therapy ofAlzheimer's disease and for the treatment of amyotrophic lateralsclerosis. They are likewise suitable as therapeutic agents for thetreatment of brain and spinal traumas. In particular, however, they aresuitable as medicament active ingredients for anxiolytics,antidepressants, antipsychotics, neuroleptics, antihypertonics and/orfor positively influencing obsessive-compulsive disorder (OCD), anxietystates and physiological changes associated with anxiety states, suchas, for example, tachycardia, tremor or sweating, panic attacks,psychoses, schizophrenia, inclusive schizotypical personality disorders,for the prevention of schizophrenia in first degree relatives andtreatment-resistant schizophrenia, anorexia, delusional obsessions,agoraphobia, migraines, cognitive deficits, Alzheimer's disease andother forms of dementia, for example vascular dementia, Lewy bodydementia and dementia in Parkinson's disease, behaviour disturbances indementia, in particular in the elderly, sleep disturbances, includingsleep apnoea, tardive dyskinesia and of psychoses in tardive dyskinesia,learning disorders, age-dependent memory disorders, attention deficitdisorders with hyperactivity and behaviour disorders, eating disorders,such as bulimia, drugs misuse, such as, for example, of alcohol,opiates, nicotine, psychostimulants, such as, for example, cocaine oramphetamines, disturbances of sexual function, aggression disorders inyouths and adults, conditions of pain of all types and fibromyalgia.

[0015] The compounds of the formula I are suitable for the treatment ofextrapyramidal side effects (EPS) of neuroleptics. EPS are characterisedby Parkinson's-like syndromes, acathisia and dystonic reactions (forexample described in EP 337136 for 5-HT₂ antagonists).

[0016] They are furthermore suitable for the treatment of anorexianervosa, angina, Reynaud's phenomenon, coronary vasospasms, in theprophylaxis of migraines (for example described in EP 208235 for 5-HT₂antagonists), pain and neuralgia (for example described in EP 320983 for5-HT₂ antagonists), for the treatment of Rett syndrome with autistictraits, of Asperger syndrome, of autism and autistic disorders, inconcentration deficit states, development disorders, hyperactivitystates with mental underdevelopment and stereotypical behaviour states(for example described in WO 9524194 for 5-HT₂ antagonists).

[0017] The compounds according to the invention are particularlysuitable for the treatment of schizophrenia.

[0018] They are furthermore suitable for the treatment of endocrineillnesses, such as hyperprolactinemia, furthermore in vasospasms,thrombotic illnesses (for example described in WO 9946245 for 5-HT₂antagonists), hyper-tension and gastrointestinal illnesses.

[0019] They are furthermore suitable for the treatment of cardiovascularillnesses and extrapyramidal symptoms, as described in WO 99/11641, onpage 2, lines 24-30, for 5-HT₂ antagonists.

[0020] They can furthermore be employed as intermediates in thepreparation of further medicament active ingredients.

[0021] The invention relates to the piperazinylcarbonylquinolines and-isoquino-lines of the formula I and to their physiologically acceptableacid-addition salts. The invention also relates to the solvates, forexample hydrates or alcoholates, of these compounds.

[0022] The term solvates of the compounds of the formula I is taken tomean adductions of inert solvent molecules onto the compounds of theformula I which form owing to their mutual attractive force. Solvatesare, for example, mono- or dihydrates or addition compounds withalcohols, such as, for example, with methanol or ethanol.

[0023] The invention relates to the compounds of the formula I and theirsalts and solvates according to Claim 1 and to a process for thepreparation of compounds of the formula I and their salts and solvates,characterised in that

[0024] a) a compound of the formula II

[0025] in which L is Cl, Br, I or a free or reactively functionallymodified OH group,

[0026] and R² is as defined in Claim 1, is reacted with a compound ofthe formula III

[0027] in which R¹ and alk are as defined in Claim 1, or

[0028] b) a compound of the formula IV

[0029] in which R² is as defined in Claim 1, is reacted with a compoundof the formula V

L-alk-R¹  V

[0030] in which L is Cl, Br, I or a free or reactively functionallymodified OH group, and R¹ and alk are as defined in Claim 1, or

[0031] c) if desired, one of the radicals R², R³, R⁴ and/or R⁵ isconverted into another radical R², R³, R⁴ and/or R⁵ by, for example,cleaving an OA group to form an OH group and/or converting a CHO groupinto a CN group, and/or

[0032] a resultant base of the formula I is converted into one of itssalts by treatment with an acid.

[0033] The invention also relates to the compounds of the formula Iaccording to Claim 1 and to their physiologically acceptable salts andsolvates as medicament active ingredients.

[0034] The invention furthermore relates to the compounds of the formulaI according to Claim 1 and their physiologically acceptable salts orsolvates as inhibitors of the 5-HT_(2A) receptor.

[0035] The invention also relates to the compounds of the formula I andtheir enantiomers and diastereomers and to their salts.

[0036] For all radicals which occur more than once, such as, forexample, A or Hal, their meanings are independent of one another.

[0037] The radical A is alkyl and has 1 to 6, preferably 1, 2, 3 or 4,in particular 1 or 2, carbon atoms. Alkyl is therefore in particular,for example, methyl, furthermore ethyl, n-propyl, isopropyl, n-butyl,sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or3-methylbutyl, 1,1-, 1,2- or 2,2-dimethyl-propyl, 1-ethylpropyl, hexyl,1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl,1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, furthermoretrifluoromethyl or pentafluoroethyl.

[0038] Acyl preferably has 1-6 carbon atoms and is, for example, formyl,acetyl, propionyl, butyryl, furthermore trifluoroacetyl orpentafluoropropionyl. acyl is particularly preferably acetyl

[0039] alk is alkylene having 1, 2, 3, 4, 5 or 6 carbon atoms, isunbranched or branched and is preferably methylene, ethylene, propylene,butylene or pentylene. alk is very particularly preferably ethylene.

[0040] OA is preferably methoxy, trifluoromethoxy, furthermore alsoethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy ortert-butoxy.

[0041] Het¹ is a monocyclic or bicyclic, unsaturated heterocyclic ringsystem having from 5 to 10 ring members which is unsubstituted ormonosubstituted or disubstituted by Hal, A, OA or OH and which containsone, two or three identical or different hetero atoms, such as nitrogen,oxygen and sulfur

[0042] Het¹ is preferably 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or3-pyrrolyl, 1-, 2, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4-or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5- thiazolyl, 3-, 4- or5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl,furthermore preferably 1,2,3-triazol-1-, 4- or -5-yl, 1,2,4-triazol-1-,-3- or 5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl,1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl,1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 2-, 3-, 4-,5- or 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 3- or 5-pyridazinyl,pyrazinyl, 2,-, 3-, 4-, 5- 6- or 7-benzo-furyl, 2-, 3-, 4-, 5:-, 6- or7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 2-, 4- or 5-benzimidazolyl,1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-,4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolyl, or2-, 4-, 5-, 6-, 7- or 8-quinazo-linyl.

[0043] Hal is fluorine, chlorine, bromine or iodine, in particularfluorine or chlorine. Hal is very particularly preferably fluorine.

[0044] R¹ is a phenyl or naphthyl radical, each of which isunsubstituted or substituted by R³ and/or R⁴, or Het¹, where Het¹ hasone of the meanings mentioned above, and R³ and R⁴ have one of themeanings mentioned below.

[0045] R¹ is preferably unsubstituted or monosubstituted phenyl ornaphthyl, in detail preferably phenyl, o-, m- or p-tolyl, o-, m- orp-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl,o-, m- or p-tert-butylphenyl, o-, m- or p-trifluoromethylphenyl, o-, m-or p-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- orp-(trifluoromethoxy)phenyl, o-, m- or p-cyanophenyl, o-, m- orp-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-fluorophenyl, o-,m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- orp-(difluoromethoxy)phenyl, o-, m- or p- (fluoromethoxy)phenyl,furthermore preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl,2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2-chloro-3-methyl-,2-chloro-4-methyl-, 2-chloro-5-methyl-, 2-chloro-6-methyl-,2-methyl-3-chloro-, 2-methyl-4-chloro-, 2-methyl-5-chloro-,2-methyl-6-chloro-, 3-chloro-4-methyl-, 3-chloro-5-methyl- or3-methyl4-chlorophenyl, 2-bromo-3-methyl-, 2-bromo4-methyl-,2-bromo-5-methyl-, 2-bromo-6-methyl-, 2-methyl-3-bromo-,2-methyl-4-bromo-, 2-methyl-5-bromo-, 2-methyl-6-bromo-,3-bromo-4-methyl-, 3-bromo-5-methyl- or 3-methyl-4-bromophenyl, 2,4- or2,5-dinitrophenyl, 2,4- or 3,4-dimethoxyphenyl, 3-nitro4-chlorophenyl,2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl,2,4,6-tri-tert-butylphenyl, furthermore preferably2-nitro4-(trifluoromethyl)-phenyl, 3,5-di(trifluoromethyl)phenyl,2,4-dimethylphenyl, 2-hydroxy-3,5-dichlorophenyl, 2-fluoro-5- or4-fluoro-3-(trifluoromethyl)phenyl, 4-chloro-2- or4-chloro-3-(trifluoromethyl)-, 2-chloro-4- or2-chloro-5-(trifluoromethyl)-phenyl, 4-bromo-2- or4-bromo-3-(trifluoromethyl)phenyl, p-iodophenyl,2-nitro-4-methoxyphenyl, 2,5-dimethoxy4-nitrophenyl,2-methyl-5-nitro-phenyl, 2,4-dimethyl-3-nitrophenyl,4-fluoro-3-chlorophenyl, 4-fluoro-3,5-dimethylphenyl,2-fluoro4-bromophenyl, 2,5-difluoro-4-bromophenyl,2,4-dichloro-5-methylphenyl, 3-bromo-6-methoxyphenyl,3-chloro-6-methoxy-phenyl, 2-methoxy-5-methylphenyl or2,4,6-triisopropylphenyl. R¹ is very particularly preferably4-fluorophenyl.

[0046] R² is a quinolinyl or isoquinolinyl radical which isunsubstituted or substituted by R⁵ and/or R⁶, where R⁵ and R⁶ may haveone of the above-mentioned meanings, and the linking of the quinolinylradical can take place in the 2-, 3-, 4-, 5-, 6-, 7- or 8-position andthe linking of the isoquinolinyl radical can take place in the 1-, 3-,4-, 5-, 6-, 7- or 8-position. R² is particularly preferablyisoquinolin-1-yl, isoquinolin-3-yl, quinolin-2-yl or quinolin-8-yl.

[0047] R³ and R⁴ are each, independently of one another, preferably H,Hal, alkyl having 1-6 carbon atoms, alkoxy having 1-6 carbon atoms orhydroxyl, furthermore cyano or acyl.

[0048] R³ is preferably H, Hal, A, OA, OH, CN or acyl. R⁴ is preferablyH. R³ is very particularly preferably Hal.

[0049] R⁵ and R⁶ are each, independently of one another, preferably H,CN, acyl, Hal, A, OA, OH, CONH₂, CONHA or CONA₂, where A and acyl haveone of the meanings indicated above. R⁵ is preferably H. R⁶ ispreferably H.

[0050] Accordingly, the invention relates in particular to the compoundsof the formula I in which at least one of the said radicals has one ofthe preferred meanings indicated above. Some preferred groups ofcompounds may be expressed by the following sub-formulae Ia to Ie whichcorrespond to the formula I and in which the radicals not denoted moreprecisely are as defined for the formula I, but in which

[0051] in Ia R¹ is a phenyl radical which is unsubstituted orsubstituted by R³ and/or R⁴;

[0052] in Ib alk is ethylene;

[0053] in Ic R¹ is a phenyl radical which is unsubstituted orsubstituted by R³ and/or R⁴, and

[0054] alk is ethylene;

[0055] in Id R³ is Hal and

[0056] R⁴ is H;

[0057] in Ie R¹ is a phenyl radical which is unsubstituted orsubstituted by R³ and/or R⁴,

[0058] alk is ethylene,

[0059] R³ is Hal and

[0060] R⁴ is H.

[0061] The compounds of the formula I and also the starting materialsfor their preparation are, in addition, prepared by methods known perse, as described in the literature (for example in standard works suchas Houben-Weyl, Methoden der Organischen Chemie [Methods of OrganicChemistry], Georg Thieme Verlag, Stuttgart; Organic Reactions, JohnWiley & Sons, Inc., New York), to be precise under reaction conditionswhich are known and suitable for said reactions. Use can also be madehere of variants which are known per se, but are not mentioned here ingreater detail.

[0062] The starting materials for the claimed process may, if desired,also be formed in situ by not isolating them from the reaction mixture,but instead immediately converting them further into the compounds ofthe formula I. On the other hand, it is possible to carry out thereaction stepwise.

[0063] In the compounds of the formulae II and V, the radical L ispreferably Cl or Br; however, it may also be I, OH or also preferably areactively functionally modified OH group, in particularalkylsulfonyloxy having 1-6 carbon atoms (for examplemethanesulfonyloxy) or arylsulfonyloxy having 6-10 carbon atoms (forexample benzenesulfonyloxy, p-toluenesulfonyloxy, 1- or2-naphthalenesulfonyloxy) or alternatively trichloromethoxy, alkoxy,such as, for example, methoxy, ethoxy, propoxy or butoxy, furthermorealso phenoxy.

[0064] The compounds of the formula I can preferably be obtained byreacting compounds of the formula II with compounds of the formula III.

[0065] The starting materials of the formulae II and III are generallyknown; the compounds of the formulae II and III which are not known canreadily be prepared analogously to the known compounds.

[0066] The reaction of the compounds II and III proceeds by methods asare known from the literature for the alkylation or acylation of amines.However, it is also possible to react the compounds in the presence ofan inert solvent. Examples of suitable solvents are hydrocarbons, suchas benzene, toluene or xylene; ketones, such as acetone or butanone;alcohols, such as methanol, ethanol, isopropanol or n-butanol; ethers,such as tetrahydrofuran (THF) or dioxane; amides, such asdimethylformamide (DMF) or N-methylpyrrolidone; nitriles, such asacetonitrile, if desired also mixtures of these solvents with oneanother or mixtures with water. The addition of an acid-binding agent,for example an alkali or alkaline earth metal hydroxide, carbonate orbicarbonate or of another salt of a weak acid of the alkali metals oralkaline earth metals, preferably of potassium, sodium or calcium, orthe addition of an organic base, such as triethylamine,dimethyl-aniline, pyridine or quinoline, or of an excess of piperazinederivative of the formula II, may be favourable. Depending on theconditions used, the reaction time is between a few minutes and 14 days,and the reaction temperature is between about 0 and 150°, normallybetween 20 and 130°.

[0067] Furthermore, compounds of the formula I can be prepared byreacting amines of the formula IV with a component of the formula Vcontaining the radical R¹.

[0068] The respective components are generally known or can be preparedby known processes as already described.

[0069] A resultant base of the formula I can be converted into theassociated acid-addition salt using an acid. Suitable acids for thisreaction ar those which give physiologically acceptable salts. Thus, itis possible to use inorganic acids, for example sulfuric acid,hydrohalic acids, such as hydrochloric acid or hydrobromic acid,phosphoric acids, such as orthophosphoric acid, nitric acid or sulfamicacid, furthermore organic acids, in detail aliphatic, alicyclic,araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic,sulfonic or sulfuric acids, such as formic acid, acetic acid, propionicacid, pivalic acid, diethylacetic acid, malonic acid, succinic acid,pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid,malic acid, benzoic acid, salicylic acid, 2-phenylpropionic acid, citricacid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid,methane- or ethanesulfonic acid, ethanedisulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonicacid, naphthalenemono- and -disulfonic acids and laurylsulfuric acid.

[0070] The free bases of the formula I may, if desired, be liberatedfrom their salts by treatment with strong bases, such as sodiumhydroxide, potassium hydroxide, sodium carbonate or potassium carbonate,so long as the molecule contains no further acidic groups. In thosecases where the compounds of the formula I have free acid groups, saltformation can likewise be achieved by treatment with bases. Suitablebases are alkali metal hydroxides, alkaline earth metal hydroxides ororganic bases in the form of primary, secondary or tertiary amines.

[0071] The invention furthermore relates to the medicaments according tothe invention having a 5-HT_(2A) receptor antagonistic action for thetreatment of psychoses, schizophrenia, depression, neurologicaldisorders, memory disorders, Parkinson's disease, amyotrophic lateralsclerosis, Alzheimers disease, Huntington's disease, eating disorders,such as bulimia, anorexia nervosa, premenstrual syndrome and/or forpositively influencing obsessive-compulsive disorder (OCD).

[0072] The invention furthermore relates to pharmaceutical preparationsprepared, in particular, by non-chemical methods which comprise at leastone compound of the formula I and/or one of its physiologicallyacceptable salts or solvates and at least one pharmaceuticallyacceptable assistant. The compounds of the formula I here can beconverted into a suitable dosage form together with at least one solid,liquid and/or semi-liquid excipient or assistant and if desired incombination with one or more further active ingredient(s).

[0073] These preparations can be employed as medicaments in human andveterinary medicine. Suitable excipients are organic or inorganicsubstances which are suitable for enteral (for example oral), parenteralor topical application and do not react with the novel compounds, forexample water, vegetable oils, benzyl alcohols, polyethylene glycols,glycerol triacetate, gelatine, carbohydrates, such as lactose or starch,magnesium stearate, talc or Vaseline. Suitable for oral administrationare, in particular, tablets, pills, coated tablets, capsules, powders,granules, syrups, juices or drops, suitable for rectal administrationare suppositories, suitable for parenteral application are solutions,preferably oil-based or aqueous solutions, furthermore suspensions,emulsions or implants, and suitable for topical application areointments, creams or powders. The novel compounds may also belyophilised and the resultant lyophilisates used, for example, for thepreparation of injection preparations. The preparations indicated may besterilised and/or comprise auxiliaries, such as lubricants,preservatives, stabilisers and/or wetting agents, emulsifiers, salts formodifying the osmotic pressure, buffer substances, dyes, flavours and/ora plurality of further active ingredients, for example one or morevitamins.

[0074] The substances according to the invention are generallyadministered analogously to known preparations, preferably in doses ofbetween about 0.1 and 500 mg, in particular between 5 and 300 mg, perdosage unit. The daily dose is preferably between about 0.01 and 250mg/kg, in particular between 0.02 and 100 mg/kg of body weight.

[0075] However, the specific dose for each particular patient depends onan extremely wide variety of factors, for example on the efficacy of thespecific compound employed, on the age, body weight, general state ofhealth, sex, on the diet, on the time and method of administration, onthe rate of excretion, medicament combination and severity of theparticular illness to which the therapy applies. Oral administration ispreferred.

[0076] The invention furthermore relates to the use of the compoundsaccording to the invention and/or of their physiologically acceptablesalts and solvates for the preparation of a medicament, in particular amedicament having a 5-HT_(2A) receptor antagonistic action.

[0077] The invention also relates to the use of the compounds accordingto the invention and/or their physiologically acceptable salts andsolvates for the preparation of a medicament having a 5-HT_(2A) receptorantagonistic action for the treatment of schizophrenia.

[0078] The invention also relates to the use of the compounds accordingto the invention and/or of their physiologically acceptable salts andsolvates for the preparation of a medicament having a 5-HT_(2A) receptorantagonistic action for the treatment of psychoses, depression,neurological disorders, memory disorders, Parkinson's disease,amyotrophic lateral sclerosis, Alzheimer's disease, Huntington'sdisease, eating disorders, such as bulimia, anorexia nervosa,premenstrual syndrome and/or for positively influencingobsessive-compulsive disorder (OCD).

[0079] The invention furthermore relates to selective 5-HT_(2A) receptorantagonists for the treatment of psychoses, schizophrenia, depression,neurological disorders, memory disorders, Parkinson's disease,amyotrophic lateral sclerosis, Alzheimer's disease, Huntington'sdisease, eating disorders, such as bulimia, anorexia nervosa,premenstrual syndrome and/or for positively influencingobsessive-compulsive disorder (OCD).

[0080] The invention furthermore relates to selective 5-HT_(2A) receptorantagonists for the treatment of psychoses, schizophrenia, depression,neurological disorders, memory disorders, Parkinson's disease,amyotrophic lateral sclerosis, Alzheimer's disease, Huntington'sdisease, eating disorders, such as bulimia, anorexia nervosa,premenstrual syndrome and/or for positively influencingobsessive-compulsive disorder (OCD), characterised in that theantagonists do not bind to other relevant receptors. Whereas the IC₅₀ atthe 5-HT_(2A) receptor is 1 nM, for example, for the substance describedin Example 1, it is greater than 1 μM for the 5-HT_(2C) receptor, the5-HT_(1A) receptor, the 5-HT_(1B) receptor, the 5-HT_(1D) receptor andthe D₂ receptor, i.e. the affinities differ by a factor of greater than1000. In the substance class described, selectivities with respect toother G-protein-coupled receptors of from 10 to more than 1000 arefound.

[0081] The invention likewise relates to the use of a selective5-HT_(2A) antagonist for the preparation of a medicament for thetreatment of schizophrenia.

[0082] The invention also relates to the use of a selective 5-HT_(2A)antagonist for the preparation of a medicament for the treatment ofpsychoses, depresssion, neurological disorders, memory disorders,Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease,Huntington's disease, eating disorders, such as bulimia, anorexianervosa, premenstrual syndrome and/or for positively influencingobsessive-compulsive disorder (OCD).

[0083] Above and below, all temperatures are given in ° C. In theexamples below, “conventional work-up” means that the solvent is removedif necessary, water is added if necessary, the mixture is adjusted, ifnecessary, to a pH of between 2 and 10, depending on the constitution ofthe end product, the mixture is extracted with ethyl acetate ordichloromethane, the phases are separated, the organic phase is driedover sodium sulfate and evaporated, and the product is purified bychromatography on silica gel and/or by crystallisation. The purifiedcompounds are, if desired, freeze-dried.

EXAMPLE A1

[0084] Preparation of a suspension of 5-HT_(2A) receptors: Frontal ratcortex is homogenised in ice-cold buffer. The homogenate is centrifugedat 4° C. and 50,000×for 10 minutes. The pellet is re-suspended in 2.5 mlof ice-cold tris buffer, made up with 10 ml of additional buffer andcentrifuged as described. The pellet is then re-suspended in buffer anddiluted to give a homogenate which comprises 60 mg of material/ml. 0.1ml of the suspension, 100 μl of a 5 nM solution of [³H]ketanserine, 100μl of a solution of the test compound (concentration in the range from10⁻⁵ to 10⁻¹⁰ mol per litre) are introduced into the incubation tubesand made up to 1 ml with buffer. The tubes are incubated at 37°C. for 15minutes. After the incubation has been interrupted by immersing thetubes into an ice bath, the cooled suspension is filtered through aglass filter under reduced pressure. The filters are washed 3× with 5 mlof cold buffer and then transferred into scintillation tubes. Thefilters are analysed by liquid scintillation spectrometry in 8 ml ofTriton-X scintillator liquid.

Example 1

[0085] 0.9 g of 1,1′-carbonyldiimidazole is added to a solution of 1 gof isoquinoline-1-carboxylic acid in 100 ml of tetrahydrofuran (THF),and the mixture is stirred at room temperature for 2 hours. 1.6 g of1-[2-(4-fluorophenyl)ethyl]piperazine and 2.4 ml of triethylamine areadded to this mixture, which is stirred for a further 80 hours.ConventionaL work-up gives{4-[2-(4-fluorophenyl)ethyl]piperazin-1-yl}isoquinolin-1-ylmethanone.

[0086] For salt formation, 1N hydrochloric acid is added to a solutionof {4-[2-(4-fluorophenyl)ethyl]piperazin-1-yl}isoquinolin-1-ylmethanonein 60 ml of acetone and 50 ml of ether until crystals form. Whencrystallisation is complete, the mother liquor is filtered off, and theprecipitate is washed with ether and dried, giving{4-[2-(4-fluorophenyl)ethyl]piperazin-1-yl}isoquinolin-1-ylmethanone,hydrochloride, m.p. 238-240°.

Example 2

[0087] Analogously to Example 1, quinaldic acid is reacted with1-[2-(4-fluoro-phenyl)ethyl]piperazine, giving{4-[2-(4-fluorophenyl)ethyl]piperazin-1-yl}-quinolin-2-ylmethanone.

[0088] Crystallisation using 1N hydrochloric acid analogously to Example1 gives{4-[2-(4-fluorophenyl)ethyl]piperazin-1-yl}quinolin-2-ylmethanone,hydrochloride; m.p. 221-222°.

Example 3

[0089] 0.34 ml of thionyl chloride is added to a suspension of 0.4 g ofquinoline-8-carboxylic acid in THF, and the mixture is refluxed for 1hour. The mixture is then freed from solvent, and the residue(quinoline-8-carbonyl chloride) is taken up in 50 ml of dichloromethane.2.1 g of polymeric DMAP (Aldrich, Article No. 35,998-2), 0.6 ml oftriethylamine and 0.6 g of 1-[2-(4-fluoro-phenyl)ethyl]piperazine areadded to this solution, and the mixture is stirred at room temperaturefor 5 days. Conventional work-up gives{4-[2-(4-fluorophenyl)ethyl]piperazin-1 -yl}quinolin-8-ylmethanone.

[0090] Salt formation by reaction of a solution of{4-[2-(4-fluorophenyl)ethyl]-piperazin-1-yl}quinolin-8-ylmethanone in 30ml of acetone with 0.2 ml of ethanolic hydrochloric acid gives{4-[2-(4-fluorophenyl)ethyl]piperazin-1-yl}quinolin-8-ylmethanone,hydrochloride, m.p. 219-220.5°.

Example 4

[0091] Analogously to Example 3, firstly isoquinoline-3-carboxylic acidis reacted with thionyl chloride, and the resultantisoquinoline-3-carbonyl chloride is reacted with1-[2-(4-fluorophenyl)ethyl]piperazine, giving{4-[2-(4-fluoro-phenyl)ethyl]piperazin-1 -yl}isoquinolin-3-ylmethanone.

[0092] Salt formation analogously to Example 3 gives amorphous{4-[2-(4-fluoro-phenyl)ethyl]piperazin-1-yl}isoquinolin-3-ylmethanone,hydrochloride, m.p. 163-170°.

[0093] The examples below relate to pharmaceutical preparations:

Example A

[0094] Injection Vials

[0095] A solution of 100 g of an active ingredient of the formula I and5 g of disodium hydrogenphosphate in 3 l of bidistilled water isadjusted to pH 6.5 using 2N hydrochloric acid, sterile filtered,transferred into injection vials, lyophilised and sealed under sterileconditions. Each injection vial contains 5 mg of active ingredient.

Example B

[0096] Suppositories

[0097] A mixture of 20 g of an active ingredient of the formula I ismelted with 100 g of soya lecithin and 1400 g of cocoa butter, pouredinto moulds and allowed to cool. Each suppository contains 20 mg ofactive ingredient.

Example C

[0098] Solution

[0099] A solution is prepared from 1 g of an active ingredient of theformula I, 9.38 g of NaH₂PO₄×2 H₂O, 28.48 g of Na₂HPO₄×12 H₂O and 0.1 gof benzalkonium chloride in 940 ml of bidistilled water. The pH isadjusted to 6.8, and the solution is made up to 1 l and sterilised byirradiation. This solution can be used in the form of eye drops.

Example D

[0100] Ointment

[0101] 500 mg of an active ingredient of the formula I are mixed with99.5 g of Vaseline under aseptic conditions.

Example E

[0102] Tablets

[0103] A mixture of 1 kg of active ingredient of the formula I, 4 kg oflactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesiumstearate is pressed to give tablets in a conventional manner in such away that each tablet contains 10 mg of active ingredient.

Example F

[0104] Coated Tablets

[0105] Tablets are pressed analogously to Example E and subsequentlycoated in a conventional manner with a coating of sucrose, potatostarch, talc, traga-canth and dye.

Example G

[0106] Capsules

[0107] 2 kg of active ingredient of the formula I are introduced intohard gelatine capsules in a conventional manner in such a way that eachcapsule contains 20 mg of the active ingredient.

Example H

[0108] Ampoules

[0109] A solution of 1 kg of active ingredient of the formula I in 60 lof bidistilled water is transferred into ampoules, lyophilised underaseptic conditions and sealed under sterile conditions. Each ampoulecontains 10 mg of active ingredient.

1. Compounds of the formula I

in which R¹ is a phenyl or naphthyl radical which is unsubstituted orsubstituted by R³ and/or R⁴, or is Het¹, R² is a quinolinyl orisoquinolinyl radical which is unsubstituted or substituted by R⁵ and/orR⁶, R³ and R⁴ are each, independently of one another, H, Hal, A, OA, OHor CN, R⁵ and R⁶ are each, independently of one another, H, CN, acyl,Hal, A, OA, OH, CONH₂, CONHA or CONA₂, Het¹ is a monocyclic or bicyclic,unsaturated heterocyclic ring system which is unsubstituted ormonosubstituted or disubstituted by Hal, A, OA or OH and which containsone, two or three identical or different heteroatoms, such as nitrogen,oxygen and sulfur, A is alkyl having 1-6 carbon atoms, alk is alkylenehaving 1-6 carbon atoms, Hal is F, Cl, Br or l, and physiologicallyacceptable salts and solvates thereof.
 2. Compounds of the formula Iaccording to claim 1, characterised in that R¹ is a phenyl radical whichis unsubstituted or substituted by R³ and/or R⁴.
 3. Compounds of theformula I according to claim 1 or 2, characterised in that alk isethylene.
 4. Compounds of the formula I according to claim 1, 2 or 3,characterised in that R³ is halogen and R⁴ is hydrogen.
 5. Compoundsaccording to claim 1 a){4-[2-(4-fluorophenyl)ethyl]piperazin-1-yl}isoquinolin-1-yl-methanone,b) {4-[2-(4-fluorophenyl)ethyl]piperazin-1-yl}quinolin-2-ylmethanone, c){4-[2-(4-fluorophenyl)ethyl]piperazin-1-yl}quinolin-8-ylmethanone, d){4-[2-(4-fluorophenyl)ethyl]piperazin-1-yl}isoquinolin-3-yl-methanone,and physiologically acceptable salts and solvates thereof.
 6. Processfor the preparation of compounds of the formula I according to claim 1,characterised in that a) a compound of the formula II

 in which L is Cl, Br, I or a free or reactively functionally modifiedOH group,  and R² is as defined in claim 1, is reacted with a compoundof the formula III

 in which R¹ and alk are as defined in claim 1, or b) a compound of theformula IV

 in which R is as defined in claim 1, is reacted with a compound of theformula V L-alk-R¹  V  in which L is Cl, Br, I or a free or reactivelyfunctionally modified OH group, and R¹ and alk are as defined in claim1, or c) if desired, one of the radicals R², R³, R⁴ and/or R⁵ isconverted into another radical R², R³, R⁴ and/or R⁵ by, for example,cleaving an OA group to form an OH group and/or converting a CHO groupinto a CN group, and/or a resultant base of the formula I is convertedinto one of its salts by treatment with an acid.
 7. Compounds of theformula I according to claim 1 and their physiologically acceptablesalts and solvates as medicament active ingredients.
 8. Compounds of theformula I according to claim 1 and their physiologically acceptablesalts or solvates as inhibitors of the 5-HT_(2A) receptor.
 9. Medicamentactive ingredient according to claim 7 for the treatment of psychoses,schizophrenia, depression, neurological disorders, memory disorders,Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease,Huntington's disease, eating disorders, such as bulimia, anorexianervosa, premenstrual syndrome and/or for positively influencingobsessive-compulsive disorder (OCD).
 10. Pharmaceutical preparation,characterised by a content of at least one compound of the formula Iaccording to claim 1 and/or one of its physiologically acceptable saltsor solvates and at least one pharmaceutically acceptable assistant. 11.Use of compounds of the formula I according to claim 1 and/or theirphysiologically acceptable salts or solvates for the preparation of amedicament.
 12. Use of compounds of the formula I according to claim 1and/or of their physiologically acceptable salts and solvates for thepreparation of a medicament having a 5-HT_(2A) receptor antagonisticaction.
 13. Use according to claim 11 for the preparation of amedicament for the treatment of schizophrenia.
 14. Use according toclaim 11 for the preparation of a medicament for the treatment ofpsychoses, depression, neurological disorders, memory disorders,Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease,Huntington's disease, eating disorders, such as bulimia, anorexianervosa, premenstrual syndrome and/or for positively influencingobsessive-compulsive disorder (OCD).
 15. Selective 5-HT_(2A) receptorantagonists for the treatment of psychoses, schizophrenia, depression,neurological disorders, memory disorders, Parkinson's disease,amyotrophic lateral sclerosis, Alzheimer's disease, Huntington'sdisease, eating disorders, such as bulimia, anorexia nervosa,premenstrual syndrome and/or for positively influencingobsessive-compulsive disorder (OCD).
 16. Selective 5-HT_(2A) receptorantagonists for the treatment of psychoses, schizophrenia, depression,neurological disorders, memory disorders, Parkinson's disease,amyotrophic lateral sclerosis, Alzheimer's disease, Huntington'sdisease, eating disorders, such as bulimia, anorexia nervosa,premenstrual syndrome and/or for positively influencingobsessive-compulsive disorder (OCD), characterised in that theantagonists do not bind to the 5-HT_(2C), 5-HT_(1A), 5-HT_(1B) and5-HT_(1D) receptor.
 17. Use of a selective 5-HT_(2A) antagonist for thepreparation of a medicament for the treatment of schizophrenia.
 18. Useof a selective 5-HT_(2A) antagonist for the preparation of a medicamentfor the treatment of psychoses, depression, neurological disorders,memory disorders, Parkinson's disease, amyotrophic lateral sclerosis,Alzheimer's disease, Huntington's disease, eating disorders, such asbulimia, anorexia nervosa, premenstrual syndrome and/or for positivelyinfluencing obsessive-compulsive disorder (OCD).